Inhibition of cGMP-dependent protein kinase by the regulatory subunit of photoreceptor cGMP phosphodiesterase

cGMP-dependent protein kinases (PKGs) mediate many cellular processes including neuronal signaling. The functional significance of PKG I in neurons is emphasized by recent findings that indicate its broad distribution in the brain and eye. In the photosensitive neurons (photoreceptors), the inhibitory γ subunit (Pγ) of the central effector cGMP phosphodiesterase (PDE6) modulates visual signaling through a cooperative binding together with cGMP to the regulatory domains of the PDE6 catalytic subunits. Here, we report that PKG Iα is inhibited by Pγ. Kinase activity assays showed that the maximum inhibition of PKG by Pγ was similar to that by a specific PKG inhibitor. The N-terminal half (Pγ1-61) containing a polycationic region was found to be a more potent PKG inhibitor as compared to the full-length molecule, whereas the C-terminus (Pγ62-87) did not inhibit PKG activity. Pγ itself was not found to be a phosphorylation substrate of PKG. This finding may provide important insights into the modulations in neurons and other cells.